Respiratory Syncytial Virus

Abstract

Human respiratory syncytial virus (HRSV) is a ubiquitous ribonucleic acid (RNA) virus that represents the leading cause of acute lower respiratory infections (mainly bronchiolitis and pneumonia) in infants and young children worldwide. HRSV belongs to the Pneumovirinae subfamily within the Paramyxoviridae family of enveloped, negative‐strand RNA viruses. Epithelial cells lining the nasal passages and respiratory tract are the primary target of HRSV infection, although alveolar macrophages and dendritic cells are also infected. Infected cells respond by producing a variety of cytokines, chemokines and interferons that are involved in the inflammatory response to HRSV. Although primary HRSV infection occurs at an early age, immunity is short‐lived or incomplete and re‐infections occur throughout life. Initial efforts to develop a vaccine based on formalin‐inactivated HRSV resulted in vaccine‐enhanced disease, and there is still no licensed prophylactic HRSV vaccine available.

Key Concepts:

  • Human respiratory syncytial virus (HRSV) is the leading cause of serious respiratory tract disease in children and infants worldwide.

  • HRSV belongs to the Pneumovirinae subfamily within the Paramyxoviridae family of negative‐strand RNA viruses.

  • The HRSV genome comprises 10 genes that encode 11 viral proteins.

  • HRSV derives its name from the formation of multinucleated, fused cells (syncytia), which are the hallmark of infection of cultured cells or lung tissue.

  • Following attachment to the target cell, entry by HRSV is mediated by fusion of the viral envelope with the host cell plasma membrane at neutral pH.

  • The entire replication cycle of HRSV takes place in the cytoplasm of the infected cell.

  • Reverse genetics has permitted the recovery of infectious HRSV from complementary DNA.

  • HRSV strains disseminate rapidly worldwide, accumulating mutations predominantly in the attachment protein, probably as a consequence of immune selection.

  • Pathology associated with HRSV infections is not only the result of direct virus injury, but largely the consequence of an aberrant immune/inflammatory response.

  • Palivizumab, a neutralising monoclonal antibody directed against HRSV fusion protein, is the only product available on the market for prophylactic treatment of children at high risk of severe infection.

Keywords: negative‐strand RNA viruses; subfamily Pneumovirinae; bronchiolitis; membrane fusion; pathogenesis; vaccines; antivirals

Figure 1.

Paramyxovirus genome organisation. Gene maps for representative members of each genus of the Paramyxovirinae and Pneumovirinae subfamilies are shown. The nucleotide length of each viral genome (nt), the intergenic regions and the noncoding termini (not to scale) are shown. Genes are colour‐coded for function and the overlap between the HRSV M2 and L genes is indicated.

Figure 2.

Human respiratory syncytial virus structure. (a) Negative‐stained preparation of partially‐purified HRSV (A2 strain). Electron micrograph by Lesley Calder, National Institute for Medical Research, London, UK, reproduced at a magnification of 90 000×. (b) Schematic diagram of the HRSV virion (not to scale). The colour coding of proteins matches that of Figure . Virion diagram provided by Alfonsina Trento, ISCIII, Madrid, Spain.

Figure 3.

Human respiratory syncytial virus G glycoprotein. The full length, 298 amino acid membrane‐anchored G protein (Gm) and the 233 amino acid soluble G protein (Gs) are shown (Long strain). Gs is formed by alternative translation initiation at M48, followed by cleavage after residue 65. Inverted triangles represent N‐glycosylation sites and vertical lines indicate O‐linked glycosylation sites. Cysteine residues overlapping the central conserved domain are represented by solid circles. The lower part of the figure depicts a model of the 3‐dimensional structure of Gm. Although Gm is probably tetrameric, a dimer is shown for simplicity. Antibody epitopes and the glycosaminoglycan (GAG)‐binding site are indicated by arrows. Adapted from Melero with permission from Elsevier. Figure provided by Alfonsina Trento, ISCIII, Madrid, Spain.

Figure 4.

Human respiratory syncytial virus fusion (F) glycoprotein. (a) Hydrophobic signal peptide (SP), fusion peptide (FP) and transmembrane (TM) regions are shown as hatched boxes. The arrows indicate the double cleavage sites of F0 that yield disulphide‐linked (S–S) F2 (black) and F1 (red) chains. Heptad repeat sequences HRA and HRB are shown in green and blue, respectively. Also indicated are the locations of the F protein antigenic sites. Three‐dimensional models of the trimeric prefusion (b) and postfusion (c) structures are shown, with cleavage sites indicated by arrows. The backbone is coloured grey and a single monomer is colored to the same scheme as in part (a). Models were built using the SWISS‐MODEL server facilities (http://swissmodel.expasy.org/) and the atomic coordinates of the prefusion structure of the parainfluenza virus 5 F protein (Protein Data Bank code, 2B9B) or the postfusion structure of the parainfluenza virus 3 F protein (Protein Data Bank code, 1ZTM) as templates (Yin et al., ). Figure provided by Margarita Magro, ISCIII, Madrid, Spain.

Figure 5.

Global distribution of viruses belonging to the BA genotype with a 60 nucleotide duplication in the G protein gene. Different lineages are colour coded and for each lineage the years of circulation are shown on the right. Reproduced from Trento et al. with permission from the American Society for Microbiology. Figure provided by Alfonsina Trento.

close

References

Alwan WH, Record FM and Openshaw PJM (1992) CD4+ T‐cells clear virus but augment disease in mice infected with respiratory syncytial virus. Comparison with the effects of CD8+ T‐cells. Clinical and Experimental Immunology 88: 527–536.

Bembridge GP, Rodriguez N, García‐Beato R et al. (2000) Respiratory syncytial virus infection of gene gun vaccinated mice induces Th2‐driven pulmonary eosinophilia even in the absence of sensitization to the fusion (F) or attachment (G) protein. Vaccine 19: 1038–1046.

Bermingham A and Collins PL (1999) The M2‐2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription. Proceedings of the National Academy of Sciences of the USA 96: 11259–11264.

Bhella D, Ralph A, Murphy LB and Yeo RP (2002) Significant differences in nucleocapsid morphology within the Paramyxoviridae. Journal of General Virology 83: 1831–1839.

Bukreyev A, Whitehead SS, Murphy BR and Collins PL (1997) Recombinant respiratory syncytial virus from which the entire SH gene has been deleted grows efficiently in cell culture and exhibits site‐specific attenuation in the respiratory tract of the mouse. Journal of Virology 71: 8973–8982.

Cane PA, Matthews DA and Pringle CR (1994) Analysis of respiratory syncytial virus strain variation in successive epidemics in one city. Journal of Clinical Microbiology 32: 1–4.

Carter SD, Dent KC, Atkins E et al. (2010) Direct visualization of the small hydrophobic protein of human respiratory syncytial virus reveals the structural basis for membrane permeability. FEBS Letters 584: 2786–2790.

Chanock R, Roizman B and Myers R (1957) Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). I. Isolation, properties and characterization. American Journal of Hygiene 66: 281–290.

Chapman J, Abbott E, Alber DG et al. (2007) RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrobial Agents and Chemotherapy 51: 3346–3353.

Cianci C, Langley DR, Dischino DD et al. (2004) Targeting a binding pocket within the trimer‐of‐hairpins: small molecule inhibition of viral fusion. Proceedings of the National Academy of Sciences of the USA 101: 15046–15051.

Collins PL, Hill MG, Camargo E et al. (1995) Production of infectious human respiratory syncytial virus from cloned cDNA confirms an essential role for the transcription elongation factor from the 5′ proximal open reading frame of the M2 mRNA in gene expression and provides a capability for vaccine development. Proceedings of the National Academy of Sciences of the USA 92: 11563–11567.

Delgado MF, Coviello S, Monsalvo AC et al. (2009) Lack of antibody affinity maturation due to poor Toll‐like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nature Medicine 15: 34–41.

DeVinzenzo J, Lambkin‐Williams R, Wilkinson T et al. (2010) A ramdonized, double blind, placebo‐controlled study of an RNAi‐based theraphy directed against repiratory syncytial virus. Proceedings of the National Academy of Sciences of the USA 107: 8800–8805.

Escribano‐Romero E, Rawling J, García‐Barreno B and Melero JA (2004) The soluble form of human respiratory syncytial virus attachment protein differs from the membrane‐bound form in its oligomeric state but is still capable of binding to cell surface proteoglycans. Journal of Virology 78: 3524–3532.

Falsey AR, Hennessey PA, Formica MA, Cox C and Walsh EE (2005) Respiratory syncytial virus infection in elderly and high‐risk adults. New England Journal of Medicine 352: 1749–1759.

Fearns R and Collins PL (1999) Role of the M2‐1 transcription antitermination protein of respiratory syncytial virus in sequential transcription. Journal of Virology 73: 5852–5864.

Feldman SA, Audet S and Beeler JA (2000) The fusion glycoprotein of human respiratory syncytial virus facilitates virus attachment and infectivity via an interaction with cellular heparan sulphate. Journal of Virology 74: 6442–6447.

Glezen WP, Taber LH, Frank AL and Kasel JA (1986) Risk of primary infection and reinfection with respiratory syncytial virus. American Journal of Diseases of Children 140: 543–546.

González‐Reyes L, Ruiz‐Argüello MB, García‐Barreno B et al. (2001) Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proceedings of the National Academy of Sciences of the USA 98: 9859–9864.

van den Hoogen BG, de Jong JC, Groen J et al. (2001) A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nature Medicine 7: 719–724.

IMpact‐RSV Study Group (1998) Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high risk infants. Pediatrics 102: 531–537.

Kim HW, Canchola JG, Brandt CD et al. (1969) Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. American Journal of Epidemiology 89: 422–434.

Llorente MT, Taylor IA, López‐Viñas E et al. (2008) Structural properties of the human respiratory syncytial virus P protein: evidence for an elongated homotetrameric molecule that is the smallest orthologue within the family of paramyxovirus polymerase cofactors. Proteins 72: 946–958.

Marty A, Meanger J, Mills J, Shields B and Ghildyal R (2004) Association of matrix protein of respiratory syncytial virus with the host cell membrane of infected cells. Archives of Virology 149: 199–210.

Melero JA (2007) Molecular biology of human respiratory syncytial virus. In: Cane PA (ed.) Perspectives in Medical Virology. 14. Respiratory Syncytial Virus. The Netherlands: Elsevier.

Moghaddam A, Olszewska W, Wang B et al. (2006) A potential molecular mechanism for hypersensitivity caused by formalin‐inactivated vaccines. Nature Medicine 12: 905–907.

Money VA, McPhee HK, Mosely JA, Sanderson JM and Yeo RP (2009) Surface features of a Mononegavirales matrix protein indicate sites of membrane interaction. Proceedings of the National Academy of Sciences of the USA 106: 4441–4446.

Nair H, Nokes DJ, Gessner BD et al. (2010) Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta‐analysis. Lancet 375: 1545–1555.

Poch O, Blumberg BM, Bougueleret L and Tordo N (1990) Sequence comparison of five polymerases (L proteins) of unsegmented negative‐strand RNA viruses: theoretical assignment of functional domains. Journal of General Virology 71: 1153–1162.

Polack FP, Irusta PM, Hoffman SJ et al. (2005) The cysteine‐rich region of respiratory syncytial virus attachment protein inhibits innate immunity elicited by the virus and endotoxin. Proceedings of the National Academy of Sciences of the USA 102: 8996–9001.

Prince GA, Hemming VG, Horswood RL and Chanock RM (1985) Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in the cotton rat. Virus Research 33: 193–206.

Roymans D, De Bondt HL, Arnoult E et al. (2010) Binding to a potent small‐molecule inhibitor of six‐helix bundle formation requires interactions with both heptad‐repeats of the RSV fusion protein. Proceedings of the National Academy of Sciences of the USA 107: 308–313.

Russell CJ, Jardetzky TS and Lamb RA (2001) Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion. EMBO Journal 20: 4024–4034.

Spann KM, Tran KC, Chi B, Rabin R and Collins PL (2004) Suppression of the induction of alpha, beta and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages. Journal of Virology 78: 4363–4369.

Srikiatkhachorn A and Braciale TJ (1997) Virus‐specific CD8+ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. Journal of Experimental Medicine 186: 421–432.

Tawar RG, Duquerroy S, Vonrhein C et al. (2009) Crystal structure of a nucleocapsid‐like nucleoprotein‐RNA complex of respiratory syncytial virus. Science 326: 1279–1283.

Taylor G, Stott EJ, Bew M et al. (1984) Monoclonal antibodies protect against respiratory syncytial virus infection in mice. Immunology 521: 137–142.

Tran TL, Castagné N, Dubosclard V et al. (2009) The respiratory syncytial virus M2‐1 protein forms tetramers and interacts with RNA and P in a competitive manner. Journal of Virology 83: 6363–6374.

Trento A, Casas I, Calderón A et al. (2010) Ten years of global evolution of the human respiratory syncytial virus BA genotype with a 60‐nucleotide duplication in the G protein gene. Journal of Virology 84: 7500–7512.

Villanueva N, Hardy R, Asenjo A, Yu Q and Wertz G (2000) The bulk of the phosphorylation of human respiratory syncytial virus phosphoprotein is not essential but modulates viral RNA transcription and replication. Journal of General Virology 81: 129–133.

Wright PF, Karron RA, Belshe RB et al. (2007) The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of line, attenuated, respiratory syncytial virus vaccines. Vaccine 25: 7372–7378.

Yin HS, Paterso RG, Wen X, Lamb RA and Jardetzky TS (2005) Structure of the uncleaved ectodomain of the paramyxovirus (hPIV3) fusion protein. Proceedings of the National Academy of Sciences of the USA 102: 9288–9293.

Yin HS, Wen X, Paterson RG, Lamb RA and Jardetzky TS (2006) Structure of the parainfluenza virus 5 F protein in its metastable, pre‐fusion conformation. Nature 439: 38–44.

Zhang L, Peeples ME, Boucher RC, Collins PL and Pickles RJ (2002) Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology. Journal of Virology 76: 5654–5666.

Further Reading

Collins PL and Crowe JE (2007) Respiratory syncytial virus and metapneumovirus. In: Knipe DM, Howley PM, Griffin DE et al. (eds) Fields Virology, 5th edn, pp. 1601–1646. Philadelphia, PA: Lippincott‐Raven.

Collins PL and Graham BS (2008) Viral and host factors in human respiratory syncytial virus pathogenesis. Journal of Virology 82: 2040–2055.

Conzelmann KK (2004) Reverse genetics of mononegavirales. Current Topics in Microbiology and Immunology 283: 1–41.

Cowton VM, McGivern DR and Fearns R (2006) Unravelling the complexities of respiratory syncytial virus RNA synthesis. Journal of General Virology 87: 1805–1821.

Lamb RA and Jardetzky TS (2007) Structural basis of virus invasion: lessons from paramyxovirus F. Current Opinion in Structural Biology 17: 427–436.

Nokes JD and Cane PA (2008) New strategies for control of respiratory syncytial virus infection. Current Opinion in Infectious Disease 21: 639–643.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Rawling, Joanna, and Melero, José A(Apr 2011) Respiratory Syncytial Virus. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000429.pub3]